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Adipocyte and Cell Biology

Testosterone is sequestered in dysfunctional adipose tissue, modifying androgen-responsive genes

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Abstract

Background/objective

The recognized association between male hypogonadism and obesity has multifactorial implications on adipose tissue (AT) physiology. The fat solubility of testosterone (T) suggests a sequestration process in fat depots, leading to reduced circulating levels of T in obesity. Several evidence suggest that steroids play a two-sided inhibitory role on adipogenesis by locally decreasing lipid accumulation and by stimulating lipolysis. The current study investigates T trafficking and activity in dysfunctional AT.

Subjects/methods

Samples of subcutaneous AT (SAT) were obtained from explants from lipoaspirate plastic surgery in six obese and six normal weight male patients. Experimental procedures on both SAT explants and insulin-resistant (IR) 3T3-L1 adipocytes were performed, including real-time PCR and mass-spectrometry quantification.

Results

A significant deregulation of gene responsiveness to androgens in IR cells and obese SAT was observed (all p < 0.05), together with reduced T release after adrenergic stimulation (−10% compared with −55% in lean SAT, p = 0.021). Higher concentrations of intracellular T and estradiol in obese SAT were also observed (2.4 vs. 1.3 ng/g, p = 0.013 and 0.075 vs. 0.22 ng/g, p = 0.004, respectively). Testosterone accumulation resulted in even lower expression in androgen-responsive genes involved in lipolytic and anti-adipogenic pathways from both in vitro and ex vivo experiments.

Conclusions

These results suggest an altered response of dysfunctional fat cells to testosterone stimulation, which normally favors lipolysis and induces an anti-adipogenic effect. The considerable reduction of lipolytic T release after adrenergic stimulation in obese SAT contributes to AT dysfunction, in a feedforward loop further reducing T levels in obese hypogonadal males.

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Fig. 1: Testosterone cromatography in adipose tissue.
Fig. 2: Testosterone content and release from ex-vivo and in vitro samples.
Fig. 3: Gene expression in human samples of subcutaneous adipose tissue from lean (empty bars) and obese (gray bars) subjects.
Fig. 4: Gene expression in normal (empty bars) and insulin-resistant (gray bars) 3T3-L1 adipocytes.

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Author notes

  1. These authors contributed equally: Andrea Di Nisio, Iva Sabovic

Authors and Affiliations

  1. Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy

    Andrea Di Nisio, Iva Sabovic, Luca De Toni, Maurizio De Rocco Ponce & Carlo Foresta

  2. Familial Cancer Clinic, Veneto Institute of Oncology (IOV-IRCSS), Padua, Italy

    Maria Santa Rocca

  3. Department of Pharmaceutical Science, University of Padova, via Marzolo 5, 35128, Padua, Italy

    Stefano Dall’Acqua

  4. Burn Unit and Plastic Surgery, University Hospital of Padova, Padua, Italy

    Bruno Azzena

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  1. Andrea Di Nisio
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Correspondence to Carlo Foresta.

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Di Nisio, A., Sabovic, I., De Toni, L. et al. Testosterone is sequestered in dysfunctional adipose tissue, modifying androgen-responsive genes. Int J Obes 44, 1617–1625 (2020). https://doi.org/10.1038/s41366-020-0568-9

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